Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, 11794, USA.
Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, 11794, USA.
Nat Commun. 2019 Jun 14;10(1):2625. doi: 10.1038/s41467-019-10374-y.
Enormous efforts have been made to target metabolic dependencies of cancer cells for developing new therapies. However, the therapeutic efficacy of glycolysis inhibitors is limited due to their inability to elicit cell death. Hexokinase 2 (HK2), via its mitochondrial localization, functions as a central nexus integrating glycolysis activation and apoptosis resilience. Here we identify that K63-linked ubiquitination by HectH9 regulates the mitochondrial localization and function of HK2. Through stable isotope tracer approach and functional metabolic analyses, we show that HectH9 deficiency impedes tumor glucose metabolism and growth by HK2 inhibition. The HectH9/HK2 pathway regulates cancer stem cell (CSC) expansion and CSC-associated chemoresistance. Histological analyses show that HectH9 expression is upregulated and correlated with disease progression in prostate cancer. This work uncovers that HectH9 is a novel regulator of HK2 and cancer metabolism. Targeting HectH9 represents an effective strategy to achieve long-term tumor remission by concomitantly disrupting glycolysis and inducing apoptosis.
为了开发新的治疗方法，人们已经做出了巨大的努力来针对癌细胞的代谢依赖性。然而，由于糖酵解抑制剂无法引发细胞死亡，其治疗效果有限。己糖激酶 2（HK2）通过其线粒体定位，作为整合糖酵解激活和凋亡抗性的中心枢纽发挥作用。在这里，我们发现 HectH9 通过 K63 连接的泛素化调节 HK2 的线粒体定位和功能。通过稳定同位素示踪法和功能代谢分析，我们表明 HectH9 缺乏通过 HK2 抑制阻碍肿瘤葡萄糖代谢和生长。HectH9/HK2 通路调节癌症干细胞（CSC）的扩增和 CSC 相关的化疗耐药性。组织学分析表明，在前列腺癌中 HectH9 的表达上调，并与疾病进展相关。这项工作揭示了 HectH9 是 HK2 和癌症代谢的新型调节剂。靶向 HectH9 代表了一种通过同时破坏糖酵解和诱导细胞凋亡来实现长期肿瘤缓解的有效策略。
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